Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis
Authors: Toby M. Maher, Paul Ford, Kevin K. Brown, Ulrich Costabel, Vincent Cottin, Sonye K. Danoff, Irene Groenveld, Eric Helmer, R. Gisli Jenkins, Julie Milner, Geert Molenberghs, Bjorn Penninckx, Matthew J. Randall, Bernt Van Den Blink, Ann Fieuw, Charlotte Vandenrijn, Sanda Rocak, Ineke Seghers, Lixin Shao, Amit Taneja, Garrit Jentsch, Timothy R. Watkins, Wim A. Wuyts, Michael Kreuter, Nadia Verbruggen, Niyati Prasad, Marlies S. Wijsenbeek, Daniel Chambers, Michael Chia, Tamera Corte, Ian Glaspole, Nicole Goh, Mark Holmes, Monique Malouf, Francis Thien, Elizabeth Veitch, Benjamin Bondue, Caroline Dahlqvist, Antoine Froidure, Hans Slabbynck, Wim Wuyts, Claudia Cartagena Salinas, Rosa Feijoó Seoane, Victor Martínez, Roxana Maturana, Juana Pavie Gallegos, Andres Rosenblut, Rafael Silva, Alvaro Undurraga Pereira, Martina Doubkova, Norbert Pauk, Martina Plackova, Martina Sterclova, Elisabeth Bendstrup, Saher B. Shaker, Ingrid Titlestad, Stephan Budweiser, Christian Grohé, Dirk Koschel, Michael Kreuter, Antje Prasse, Michael Weber, Hubert Wirtz, Katerina Antoniou, Zoe Daniil, Mina Gaga, Despoina Papakosta, Shinyu Izumi, Masaki Okamoto, Alfredo Guerreros Benavides, Carlos Iberico Barrera, Alejandro Manuel Peña Villalobos, Aranzazu Campo Ezquibela, Jose Manuel Cifrian Martinez, Estrella Fernandez Fabrellas, Virginia Leiro, Maria Molina-Molina, Asunción Nieto Barbero, Jacobo Sellares Torres, Claudia Valenzuela, Shih-Lung Cheng, Ping-Hung Kuo, Kang-Yun Lee, Chau-Chyun Sheu, Hakan Gunen, Nesrin Mogulkoc Bishop, Sibel Nayci, Huzaifa Adamali, Stephen Bianchi, Nazia Chaudhuri, Michael Gibbons, Simon Hart, Philip Molyneaux, Helen Parfrey, Gauri Saini, Lisa G Spencer, Sarah Wiscombe, Danielle Antin-Ozerkis, Rebecca Bascom, John Belperio, Edward Britt, John Fitzgerald, Diana Gomez Manjarres, Mark Gotfried, Nishant Gupta, David Hotchkin, Mitchell Kaye, Mary Kreider, Shahrukh Kureishy, Peter Lacamera, Lisa Lancaster, Joseph Lasky, Daniel Lorch, Hannah Mannem, Lee Morrow, Teng Moua, Anoop Nambiar, Ganesh Raghu, Rishi Raj, Murali Ramaswamy, Raghu Reddy, Tonya Russell, Mary Beth Scholand, Barry Shea, Sally Suliman, Jeff Swigris, Krishna Thavarajah, Leslie Tolle, Rade Tomic, Neal Warshoff, Lewis Wesselius, Gordon Yung, Miguel Bergna, María De Salvo, Mariano Fernandez Acquier, Alicia Rodriguez, Pablo Saez Scherbovsky, Deborah Assayag, Anil Dhar, Nasreen Khalil, Julie Morisset, Steeve Provencher, Chris Ryerson, Shane Shapera, Arnaud Bourdin, Bruno Crestani, Francois Lebargy, Martine Reynaud-Gaubert, Francesco Tommaso Bonella, Martin Claussen, Peter Hammerl, Christian Karagiannidis, Claus Keller, Winfried Randerath, Beate Stubbe, Eszter Csánky, Balazs Medgyasszay, Veronika Muller, Yochai Adir, Amir Bar-Shai, Neville Berkman, Gershon Fink, Mordechai Kramer, David Shitrit, Elena Bargagli, Stefano Gasparini, Sergio Harari, Claudia Ravaglia, Luca Richeldi, Carlo Vancheri, Masahito Ebina, Masaki Fujita, Kazuya Ichikado, Yoshikazu Inoue, Nobuhisa Ishikawa, Motoyasu Kato, Tetsuji Kawamura, Yasuhiro Kondoh, Yasuhiko Nishioka, Takashi Ogura, Isoko Owan, Takefumi Saito, Noriho Sakamoto, Koji Sakamoto, Masahiro Shirai, Takafumi Suda, Keisuke Tomii, Man Pyo Chung, Sung Hwan Jeong, Choon Sik Park, Jong Sun Park, Jin Woo Song, Soo-Taek Uh, Uriel Chavarria Martinez, Efrain Montano Gonzalez, Alicia Ramirez, Moises Eduardo Selman Lama, Paul Bresser, Henk Kramer, Remy Mostard, Esther Nossent, Marcel Veltkamp, Marlies Wijsenbeek, Lutz Beckert, Catherina L Chang, Andrew Veale, Margaret Wilsher, Michal Bednarek, Grzegorz Gasior, Grazyna Jasieniak-Pinis, Ewa Jassem, Robert Mroz, Wojciech Piotrowski, Ismail Abdullah, Anish Ambaram, Elvis Irusen, Michael Van der Linden, Richard van Zyl-Smit, Paul Williams, James Allen, Francis Averill, Elizabeth Belloli, Anne Brown, Amy Case, Sachin Chaudhary, Gerard Criner, Kevin DeBoer, Daniel Dilling, Jeffrey Dorf, Richard Enelow, Neil Ettinger, Jeremy Feldman, Kevin Gibson, Jeffrey Golden, Mark Hamblin, Gary Hunninghake, Raj Karunakara, Hyun Kim, Tracy Luckhardt, Prema Menon, Lake Morrison, Justin Oldham, Nina Patel, Shelley Schmidt, Mary Strek, Ross Summer, Robert Sussman, James Tita, Srihari Veeraraghavan, Timothy Whelan, Joseph Zibrak
Journal: JAMA (2023)

There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.